The overall aim of this proposal is to establish an integrated Center for creating high-quality reference maps of key epigenotypes in pluripotent, differentiating, and primary differentiated human cells and tissues. The Northwest Reference Epigenome Mapping Center aggregates leading experts in human embryonic stem cell (hESC) biology, lineage-specific differentiation of hESCs, and well-established differentiating and differentiated adult primary tissue systems to establish a substantial capacity for the production of purified cells and tissues for large-scale epigenomic studies. The Center integrates this capacity with an existing high-throughput genomics and informatics infrastructure operating at scale, creating unique synergies that enable genome-scale epigenetic analyses of high-value human primary and progenitor cell types. The Center will perform high-resolution, whole-genome profiling of foundational epigenotypes in project cell types including high-resolution quantification of chromatin structural remodeling, and analysis of DNA methylation at both actively remodeled and silenced regulatory DNA templates. The Center will also profile both small RNA species and conventional gene expression from all study cell types. The Center's informatics and analytical arm will manage project data and its release into consortium and public repositories, and will perform integrative analyses to elucidate the connection between major epigenotypes and dynamic cellular programming of gene expression.